The race to cure a billion people from a deadly parasitic disease — Google DeepMind

Researchers accelerate their search of life-saving treatments for leishmaniasis
“We were about to give up,” says Dr Benjamin Perry, a medicinal chemist at the Drugs for Neglected Diseases initiative (DNDi). When Perry joined the organization seven years ago, based in Geneva, Switzerland, his goal was to speed up the discovery of new treatments for two potentially fatal parasitic illnesses, Chagas disease and leishmaniasis. By and large, they achieved a lot of success. For one potential leishmaniasis drug in DNDi’s diverse portfolio, however, progress had slowed almost to a halt.
“We couldn’t find ways of making changes that improved the drug molecule,” says Perry. “It either lost all its potency as an anti-parasitic or it kind of stayed the same.”
However, things changed when Perry and his collaborators heard about DeepMind’s AI system, AlphaFold. Now, using a combination of scientific detective work and AI, the researchers have cleared a path towards turning the molecule into a real treatment for a devastating disease.
New treatments for leishmaniasis can’t come soon enough. The disease is caused by parasites of the genus Leishmania and spreads through sandfly bites in countries across Asia, Africa, the Americas, and the Mediterranean.
Visceral leishmaniasis, the most severe form, causes fever, weight loss, anemia, and enlargement of the spleen and liver. “If it’s not treated, it is fatal,” says Dr Gina Muthoni Ouattara, senior medical manager at DNDi in Nairobi, Kenya. Cutaneous leishmaniasis, the most common form, causes skin lesions and leaves lasting scars.
A patient with visceral leishmaniasis and an HIV co-infection. Credit: University of Gondar
Globally, about a billion people are at risk of leishmaniasis and each year there are 50-90,000 new cases of visceral leishmaniasis, the majority in children. While medical treatments vary by region, most are lengthy and come with significant side effects.
In Eastern Africa, the first-line treatment for visceral leishmaniasis involves a 17-day course of two injections each day, of two separate drugs, sodium stibogluconate and paromomycin, given in hospital. "Even for an adult, these injections are very painful, so you can imagine having to give these two injections to a child every day for 17 days,” says Ouattara. Before DNDi’s crucial work to develop a shorter and more effective combination therapy, this treatment lasted for 30 days.
An alternative treatment requires an intravenous infusion that needs to be kept refrigerated and administered under sterile conditions. “The most limiting thing is that all of these treatments have to be given in hospital,” says Ouattara. That adds to the costs, and means patients and their caregivers miss out on income, school, and time with their family. “It really affects communities.”
People always ask themselves, ‘Have we looked at the AlphaFold structure?’ It’s become common parlance.
DNDi’s previous efforts have already cut the amount of time visceral leishmaniasis patients spend in hospital. But the organization’s ultimate goal is to come up with an oral treatment that could be administered at a local health facility, or even at home.
That kind of radical improvement might require entirely new drugs. If you’re looking for completely new compounds to turn into treatments, where do you start?
DNDi’s approach to drug discovery in this area of research could be called “old school”, says Perry, though he maintains there’s a reason for that – it’s often the best way to discover drugs. First, researchers screen thousands of molecules to find those that show promise in attacking the disease-causing organism as a whole. Then, they tweak those molecules to try to make them more effective. “It’s a bit more ‘brute force’,” he says. “We don’t usually know how it’s doing it.”
Benjamin Perry and Gina Muthoni Ouattara. Credit: DNDi
This trial-and-error approach is the best way to find new treatments for patients, says Perry. But the optimisation stage can feel a bit like stumbling around in the dark. “You're going ‘Okay, well, I've got this chemical, just make some random changes to it’ which works sometimes,” says Perry. But with their promising leishmaniasis molecule, they’d hit a brick wall. “We’d tried that and it hadn't worked.”
With hope dwindling, DNDi sent the molecule to Michael Barrett, a professor at the University of Glasgow, UK, who for the last decade has been using a technique called metabolomics to unravel how drugs work.
“There are all sorts of chemical processes occurring in our body where we chop molecules down into their component building blocks and then rebuild them,” says Barrett. “That's the basis of life, really.” Collectively, these chemical reactions make up our metabolism. Parasites, like the one that causes leishmaniasis, have a metabolism too.
Metabolic reactions are regulated by biological catalysts known as enzymes. Many drugs work by interfering with those enzymes, so Barrett and his group look for changes in the molecules that are made during metabolic reactions to figure out what a drug is doing.
He put DNDi’s molecule on to a Leishmania parasite. “Sure enough, the metabolism changed,” he says. Barrett and his colleagues saw a big increase in one molecule whose job is to turn into phospholipids, a type of fat molecule that makes up cell membranes. Yet at the same time, the number of phospholipids actually being made was decreasing.
Barrett figured out that the enzyme that would have turned the first molecule into phospholipids was the one that was being affected by the drug. Interrupting this reaction was how the molecule was killing the parasite.
Stella Akiror and John Oseluo taking down details after checking on a patient. Credit: Lameck Ododo - DNDi
But having hurdled one obstacle, Barrett’s group hit another. They wanted to know what their target enzyme looked like, but finding its structure experimentally would be near impossible because it was a type of protein that is notorio